Nat Cell Biol 2012,
PMID: 22388891
Busino, Luca; Millman, Scott E; Scotto, Luigi; Kyratsous, Christos A; Basrur, Venkatesha; O'Connor, Owen; Hoffmann, Alexander; Elenitoba-Johnson, Kojo S; Pagano, Michele
Fbxw7α is a member of the F-box family of proteins, which function as the substrate-targeting subunits of SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complexes. Using differential purifications and mass spectrometry, we identified p100, an inhibitor of NF-κB signalling, as an interactor of Fbxw7α. p100 is constitutively targeted in the nucleus for proteasomal degradation by Fbxw7α, which recognizes a conserved motif phosphorylated by GSK3. Efficient activation of non-canonical NF-κB signalling is dependent on the elimination of nuclear p100 through either degradation by Fbxw7α or exclusion by a newly identified nuclear export signal in the carboxy terminus of p100. Expression of a stable p100 mutant, expression of a constitutively nuclear p100 mutant, Fbxw7α silencing or inhibition of GSK3 in multiple myeloma cells with constitutive non-canonical NF-κB activity results in apoptosis both in cell systems and xenotransplant models. Thus, in multiple myeloma, Fbxw7α and GSK3 function as pro-survival factors through the control of p100 degradation.
Diseases/Pathways annotated by Medline MESH: Multiple Myeloma
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Text Mining Data
Dashed line = No text mining data
Manually curated Databases
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IRef Biogrid Interaction:
RELB
—
NFKB2
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
NFKBIA
—
BTRC
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
FBXW4
—
SKP1
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
BTRC
—
BCL2L11
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
NFKB2
—
NFKB2
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
BTRC
—
SKP1
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
FBXW7
—
NOTCH1
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
CUL1
—
FBXW7
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
CUL1
—
FBXW7
(association, biochemical)
-
IRef Biogrid Interaction:
SKP1
—
FBXW7
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
SKP1
—
FBXW7
(association, biochemical)
-
IRef Biogrid Interaction:
NFKB2
—
FBXW7
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
CCNE1
—
FBXW7
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
FBXW5
—
SKP1
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
BTRC
—
NFKB1
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
BTRC
—
NFKB2
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
RBX1
—
FBXW7
(association, biochemical)
-
IRef Biogrid Interaction:
FBXW8
—
SKP1
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
FBXW2
—
SKP1
(physical association, affinity chromatography technology)
In total, 17 gene pairs are associated to this article in curated databases